Project Summary Epilepsy is the fourth most prevalent neurological disorder after stroke, Alzheimer?s disease and migraine. It is estimated that about 3 million people in the U.S. and 65 million worldwide currently live with epilepsy. While a number of anti-convulsants exist to treat single seizure episodes, no anti-epileptogenic drugs are currently available to stop disease progression. Epileptogenesis (the process by which epilepsy progresses and develops) is associated with numerous pathological changes including neuroplasticity deficits, cell death, and a reduction in seizure threshold. To investigate the transcriptional regulators that drive large-scale gene expression changes during epileptogenesis, I used a bioinformatics tool developed by my advisor called the MAGIC matrix to analyze microarray datasets of dentate granule cells laser captured after Status Epilepticus (SE) in four rat seizure models. My analysis predicts that the Polycomb catalytic subunit Enhancer of Zeste Homolog 2 (EZH2) is the principal driver of expression changes during epileptogenesis. This is significant because Polycomb plays an important role during development, where it epigenetically and stably silences genes through histone methylation. Preliminary experiments in Aim 1 demonstrate that EZH2 protein levels dramatically increase after SE, while expression of its target genes significantly decrease many days after. Additionally, inhibiting EZH2 function in vivo using the pharmacological inhibitor, UNC1999, caused epileptic animals to have more seizures with greater severity over time. In the future, I aim to determine whether promoting EZH2 activity has the potential to alter hallmarks such as neurodegeneration, occurrence of spontaneous seizures and survival. This study has the potential to be one of the first to use Polycomb regulators to modify the process of epileptogenesis.